title: Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib.
abstract: The discovery of several molecular alterations that underlie non-small cell lung cancer (NSCLC) pathogenesis has led to the development of targeted therapies. In particular, gefitinib and erlotinib have become the standard of care in patients harboring epidermal growth factor receptor mutations, while crizotinib showed an impressive efficacy in patients with ALK-positive NSCLC. Nevertheless, the occurrence of clinical resistance limits the long term results of these novel agents. The identification of the molecular mechanisms responsible for acquired resistance to targeted therapy is crucial in order to pursue the creation of rational strategies to overcome resistance. In the current review, we will focus on the acquired resistance mechanisms to EGFR-TKIs and crizotinib and the therapeutic strategies currently under study to overcome resistance.
authors.affiliation: Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture, PZ, Italy. Electronic address: tarta1@virgilio.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Tartarone
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lazzari
authors.affiliation: Hospital Pharmacy, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture, PZ, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lerose
authors.affiliation: Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture, PZ, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Conteduca
authors.affiliation: Laboratory of Clinical Research, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture, PZ, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Improta
authors.affiliation: Laboratory of Clinical Research, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture, PZ, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zupa
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bulotta
authors.affiliation: Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture, PZ, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Aieta
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gregorc
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib
keywords: ALK translocation; Epidermal growth factor receptor; Non small cell lung cancer; Primary and acquired resistance to EGFR-TKIs; Resistance to crizotinib; Targeted therapy